title: MK-677, an orally active growth hormone secretagogue, reverses diet-induced catabolism.
abstract: The reversal of diet-induced negative nitrogen balance by GH suggests a possible therapeutic role for GH treatment in catabolic patients. A double-blind, randomized, placebo-controlled, two-period cross-over study was designed to investigate whether MK-677, an orally active nonpeptide mimic of GH-releasing peptide, can reverse diet-induced protein catabolism. Eight healthy volunteers (ages 24-39 yr) were calorically restricted (18 kcal/kg.day) for two 14-day periods. During the last 7 days of each diet period, subjects received either oral MK-677 25 mg or placebo once daily. There was a 14- to 21-day washout interval between periods. During the first week of caloric restriction (i.e. diet alone), daily nitrogen losses were similar for both treatment groups (mean +/- SE; MK-677 group -2.67 +/- 0.40 g/day vs. placebo group -2.83 +/- 0.26 g/day). During the second week (diet and study drug), mean daily nitrogen balance was 0.31 +/- 0.21 g/day in the MK-677 treatment group compared with -1.48 +/- 0.21 g/day in the placebo group (P < 0.01). MK-677 improved nitrogen balance integrated over the 7 days of treatment; area under the curve day 8-14 nitrogen balance response was +2.69 +/- 5.0 (SE) for MK-677 and -8.97 +/- 5.26 g.day for placebo (P < 0.001). MK-677 produced a peak GH response of 55.9 +/- 31.7 micrograms/L after single dose (day 1 of treatment) and 22.6 +/- 9.3 micrograms/L after a week of dosing compared with placebo treatment peak GH values of approximately 9 (treatment day 1) and approximately 7 micrograms/L (treatment day 7). Following the initial 7-day caloric restriction, insulin-like growth factor-I (IGF-I) declined from 232 +/- 25 to 186 +/- 19 ng/mL in the MK-677 group and from 236 +/- 19 to 174 +/- 23 ng/mL in the placebo group. Mean IGF-I concentration increased significantly during MK-677 to 264 +/- 31 ng/mL (mean for the last 5 days of treatment) compared with 188 +/- 19 ng/mL with placebo (P < 0.01). No significant difference in IGF binding protein-2 was found between the MK-677 and placebo treatments. However, the mean in IGF binding protein-3 for the last 5 days of MK-677 treatment was also significantly increased to 3273 +/- 330 ng/mL (mean +/- SE) compared with placebo 2604 +/- 253 ng/mL (P < 0.01). Neither the serum cortisol nor the PRL response was significantly greater after 7 days of MK-677 dosing compared with 7 days of placebo. MK-677 (25 mg) was generally well tolerated and without clinically significant adverse experiences. In conclusion, MK-677 reverses diet-induced nitrogen wasting, suggesting that if these short-term anabolic effects are maintained in patients who are catabolic because of certain acute or chronic disease states, it may be useful in treating catabolic conditions.
authors.affiliation: Merck Research Laboratories, Rahway, New Jersey 07065, USA.
authors.forename: M G
authors.initials: MG
authors.lastname: Murphy
authors.forename: L M
authors.initials: LM
authors.lastname: Plunkett
authors.forename: B J
authors.initials: BJ
authors.lastname: Gertz
authors.forename: W
authors.initials: W
authors.lastname: He
authors.forename: J
authors.initials: J
authors.lastname: Wittreich
authors.forename: W M
authors.initials: WM
authors.lastname: Polvino
authors.forename: D R
authors.initials: DR
authors.lastname: Clemmons
mesh_terms: D000328:Adult; D004311:Double-Blind Method; D002149:Energy Intake; D019382:Human Growth Hormone / Q000378:metabolism*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007211:Indoles / Q000494:pharmacology*; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000097:blood; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D009584:Nitrogen / Q000378:metabolism*; D010919:Placebos; D011388:Prolactin / Q000097:blood; D011506:Proteins / Q000378:metabolism*; D013141:Spiro Compounds / Q000494:pharmacology*
chemical_list: D007211:Indoles; D018971:Insulin-Like Growth Factor Binding Protein 2; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins; D010919:Placebos; D011506:Proteins; D013141:Spiro Compounds; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D011388:Prolactin; D009584:Nitrogen; C094817:ibutamoren mesylate; D006854:Hydrocortisone